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Recommendation

EULAR recommendations for vaccination in adult


patients with autoimmune inflammatory rheumatic
diseases
S van Assen,1 N Agmon-Levin,2 O Elkayam,3,4 R Cervera,5 M F Doran,6
M Dougados,7 P Emery,8,9 P Geborek,10 J P A Ioannidis,1114 D R W Jayne,15
C G M Kallenberg,16 U Mller-Ladner,17 Y Shoenfeld,2,4 L Stojanovich,18 G Valesini,19
N M Wulffraat,20 M Bijl12

Additional tables are ABSTRACT Vaccination is an attractive method to prevent


published online only. To view Objectives To develop evidence-based European League certain infections. The efcacy of vaccinations in
these files please visit the
Against Rheumatism (EULAR) recommendations for patients with AIIRD, however, may be reduced
journal online http://ard.bmj.
com vaccination in patients with autoimmune inflammatory and there is a potential risk of ares of the under-
rheumatic diseases (AIIRD). lying AIIRD following vaccination.
For numbered affiliations
see end of article Methods A EULAR task force was composed of Our aim was to develop recommendations for
experts representing 11 European countries, consisting vaccination in patients with AIIRD in line with
Correspondence to of eight rheumatologists, four clinical immunologists, the standard operating procedures of the European
S van Assen, Department of one rheumatologist/clinical immunologist, one infectious League Against Rheumatism (EULAR), combining
Internal Medicine, Division of
Infectious Diseases, University disease physician, one nephrologist, one paediatrician/ evidence from clinical studies with expert opinion
Medical Centre Groningen, rheumatologist and one clinical epidemiologist. Key when sufcient evidence was lacking. Our recom-
AA41 P O Box 30 001, 9700 RB questions were formulated and the eligible spectrum mendations target all physicians and nurses who
Groningen, The Netherlands; of AIIRD, immunosuppressive drugs and vaccines were are involved in the care for patients with AIIRD.
s.van.assen@int.umcg.nl
defined in order to perform a systematic literature
review. A search was made of Medline from 1966 to METHODS
Accepted 4 October 2010 October 2009 as well as abstracts from the EULAR Expert Committee
Published Online First The committee consisted of eight rheumatologists
meetings of 2008 and 2009 and the American College
3 December 2010
of Rheumatology (ACR) meetings of 2007 and 2008. (OE, MFD, MD, PE, PG, UML, LS, GV), four clinical
Evidence was graded in categories IIV, the strength immunologists (NAL, RC, CGMK, YS), one rheu-
of recommendations was graded in categories AD matologist/clinical immunologist (MB), one infec-
and Delphi voting was applied to determine the level of tious disease physician (SvA), one nephrologist
agreement between the experts of the task force. (DRWJ), one paediatrician/rheumatologist (NMW)
Results Eight key questions and 13 recommendations and one clinical epidemiologist (JPAI), representing
addressing vaccination in patients with AIIRD were 11 European countries.
formulated. The strength of each recommendation was
determined. Delphi voting revealed a very high level of Definitions
agreement with the recommendations among the experts In these recommendations, the term efcacy
of the task force. Finally, a research agenda was proposed. represents the capability of a vaccine to mount a
Conclusion Recommendations for vaccination in protective immune response because vaccination
patients with AIIRD based on the currently available studies in patients with AIIRD addressing clini-
evidence and expert opinion were formulated. More cal end points are scarce. Moreover, it should be
research is needed, particularly regarding the incidence of acknowledged that in vitro immune responses
vaccine-preventable infectious diseases and the safety of may not always correlate well with clinical effec-
vaccination in patients with AIIRD. tiveness. This should be taken into account when
interpreting the available evidence for these
recommendations.
Patients with autoimmune inammatory rheu-
matic diseases (AIIRD) are at increased risk of Development of recommendations
contracting infections.110 The increased suscepti- The experts were invited to dene the AIIRD, the
bility to infection can be attributed to by any of vaccines and the immunosuppressive medications
the following: the immunosuppressive effect of which were to be used as search terms for the sys-
the underlying AIIRD, the occurrence of a locus tematic literature review. Furthermore, key ques-
minoris resistentiae as a sequel of the AIIRD and tions regarding vaccination of patients with AIIRD
the use of immunomodulatory medication to treat were formulated.
the AIIRD. The possible contribution of biological Medline (via PubMed) was searched from 1966
agents to the risk of infection is of particular inter- to October 2009 as well as the abstracts from the
est, especially since increasingly more indications meetings of EULAR 2008 and 2009 and of the
are being recognised for their use, they are increas- American College of Rheumatology (ACR) 2007
ingly being used earlier in the course of AIIRD and and 2008. As search terms, the MESH terms for the
newer agents are becoming available.1123 dened AIIRD, immunosuppressive medications

414 Ann Rheum Dis 2011;70:414422. doi:10.1136/ard.2010.137216


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Recommendation

and vaccines were combined. Only articles in English and con- (1) The vaccination status should be assessed in the initial work-up
cerning patients aged >16 years were included. Other papers that of patients with AIIRD (no grade of evidence possible; strength of
were considered relevant in the opinion of the experts could be recommendation D; Delphi vote 9.50)
added. The results of the systematic literature review (performed In order to make recommendations for the individual patient
by SvA, MB, NAL, OE) were sent to the committee before the with AIIRD, it is necessary to know which vaccines the patient
second meeting together with proposals for recommendations. received in the past according to box 2. Catch-up vaccination
Thirteen recommendations were formulated. For each recom- might be considered for missed vaccinations that are recom-
mendation we used a widely-accepted hierarchy for categorising mended for the general population. Also, adverse events and
the available evidence and the strength of the recommenda- ares of the underlying AIIRD following former vaccinations
tions (see table 1 in the online supplement). A Delphi exercise should be queried since these might be (relative) contraindica-
with closed voting followed. During this exercise the 13 recom- tions for certain future vaccinations.
mendations were separately voted on and given a score from 0
(absolutely no agreement with the proposed recommendation)
(2) Vaccination in patients with AIIRD should ideally be administered
to 10 (maximal possible support for the recommendation). The
during stable disease (no grade of evidence possible; strength of
means and SDs of the scores of the whole group were calcu-
recommendation D; Delphi vote 8.88)
lated to determine the level of agreement among the experts for
No studies have been performed comparing efcacy and
each recommendation. Finally, a research agenda was created.
harms between patients with AIIRD with stable and unstable
disease. Moreover, almost all vaccination studies in patients
RESULTS with AIIRD addressed patients with quiescent disease.
Twenty-seven eligible AIIRD, 17 immunosuppressive medications Studies that also included patients with moderate or severe
and 29 vaccines (table 1) were identied and eight key questions disease activity did not show more frequent side effects or
(box 1) were composed for the systematic literature review. The disease ares, or decreased efcacy in patients with AIIRD
task force members agreed on 13 recommendations, reaching a compared with healthy controls.2426 However, the num-
high level of agreement according to the Delphi scores (table 2). bers of patients in these studies were too small to conclude
that vaccination during active disease is safe and efcacious.
Recommendations Therefore, based on theoretical risks of disease are follow-
Each recommendation is followed in parenthesis with the grade ing vaccination in unstable patients with AIIRD, vaccination
of the evidence, the strength of the recommendation and the is preferentially administered during stable disease, according
Delphi voting score. to expert opinion.

Table 1 AIIRD, immunomodulating agents and vaccines considered in the literature search and
recommendations

AIIRD Immunomodulating agents Vaccines


Rheumatoid arthritis Corticosteroids BCG
Serum lupus erythematosus Methotrexate Cholera
Antiphospholipid syndrome Sulfasalazine Diphtheria
Adult Still disease Leflunomide Hepatitis A
Systemic sclerosis Hydroxychloroquine Hepatitis B
Sjgren syndrome Azathioprine Haemophilus influenzae b
Mixed connective tissue disease Mycophenolic acid preparations Human papillomavirus
Relapsing polychondritis Ciclosporine Influenza
Giant cell arteritis Tacrolimus Japanese encephalitis
Polymyalgia rheumatica Cyclophosphamide Measles*
Takayasu arteritis Biologicals: Mumps*
Polyarteritis nodosa TNF blocking agents Neisseria meningitidis (A/C/Y/W135, C conjugated)
ANCA-associated vasculitis Infliximab Pertussis
Microscopic polyangiitis Etanercept Poliomyelitis (parenteral and oral*)
Wegener granulomatosis Adalimumab Rabies
Churg-Strauss syndrome Rituximab Rubella*
Behet disease Tocilizumab Streptococcus pneumoniae (polysaccharide and
conjugated)
Goodpasture disease Abatacept Tetanus toxoid
Cryoglobulinaemic syndrome Anakinra Tick-borne encephalitis
Polymyositis Typhoid fever (parenteral and oral*)
Dermatomyositis Varicella zoster*
Clinically amyopathic dermatomyositis Yellow fever*
Sporadic inclusion body myositis
Antisynthetase syndrome
Eosinophilic myositis
Eosinophilic fasciitis
Spondylathropathies
Periodic fever syndromes
*Live attenuated vaccines.
AIIRD, autoimmune inflammatory rheumatic diseases; BCG, Bacillus Calmette-Gurin.

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Recommendation

(3) Live attenuated vaccines should be avoided whenever possible in of immunosuppression renders patients to be at risk for infec-
immunosuppressed patients with AIIRD (grade of evidence IV; strength tions caused by these vaccines, and this risk should be balanced
of recommendation D; Delphi vote 9.25) to the risk of (severe) infection the vaccine aims to prevent.
Live attenuated vaccines (table 1) might lead to (severe) infec- Measles, mumps and rubella (MMR) vaccine has been admin-
tions in immunosuppressed patients. It is not known what level istered without subsequent infection to paediatric patients
2 years after bone marrow transplantation27 and varicella vac-
cine has been administered without subsequent infection in
Box 1 Key questions HIV-infected children with a CD4 percentage 15% or a CD4
count 200/mm3.28 Studies are ongoing for herpes zoster vac-
cine in adult patients with HIV with a CD4 count 200/mm3
1. Is the risk of infections for which vaccines are available (http://www.clinicaltrials.gov/ct2/show/NCT00851786?term
increased in patients with autoimmune inflammatory =zostavax+hiv&rank=1) and in older patients on treatment
rheumatic diseases (AIIRD) in general, and specifically with prednisone 520 mg/day (http://www.clinicaltrials.gov/
in those with active disease and in those using ct2/show/NCT00546819?term=zostavax+corticosteroid&ra
immunomodulating agents? nk=1). The Advisory Committee on Immunization Practices
2. Do vaccines decrease the risk of infections in patients with (ACIP) stated that herpes zoster vaccine may be administered
AIIRD in general, and specifically in those with unstable to patients when treated with short-term corticosteroid therapy
disease and in those using immunomodulating agents? (<14 days); low to moderate doses of corticosteroids (<20 mg/
3. Do vaccines cause any significant harm in patients with AIIRD day of prednisone or equivalent); intra-articular, bursal or tendon
in general, and specifically in those with unstable disease and corticosteroids injections; long-term alternate-day treatment
in those using immunomodulating agents? with low to moderate doses of short-acting systemic cortico-
4. Does the timing of vaccination in relation to disease steroids; therapy with methotrexate (MTX; <0.4 mg/kg/week),
activity and receipt of immunomodulating agents affect the azathioprine (<3.0 mg/kg/day) or 6-mercaptopurine (<1.5 mg/
effectiveness of vaccination in patients with AIIRD? kg/day).29 It must be emphasised that these recommendations
5. Does the timing of vaccination in relation to disease activity are based on expert opinion only and require further investiga-
and receipt of immunomodulating agents affect important tion. The EULAR task force on vaccination recommends avoid-
harms of vaccination in patients with AIIRD? ing the use of live attenuated vaccines in immunosuppressed
6. Does revaccination with any vaccines increase the patients with AIIRD whenever possible. MMR, varicella and
effectiveness in patients with AIRD? herpes zoster vaccine might be exceptions to this rule and may
7. Does revaccination with any vaccine increase significant be considered in mildly immunosuppressed patients with AIIRD
harms in patients with AIRD? on a case-by-case basis. Temporary discontinuation of immuno-
8. Is vaccination in patients with AIIRD cost-effective? suppressive medication before vaccination with live attenuated

Table 2 Recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases with level of evidence, strength of
recommendations and results of Dephi voting per recommendation
Category of evidence Strength of Mean (SD) level
recommendation of agreement
Increased incidence Efficacy of Harms of by Delphi voting
Recommendation of VP infection vaccination vaccination (VAS)
The vaccination status should be assessed in the initial investigation of patients with D 9.50 (0.97)
AIIRD
Vaccination in patients with AIIRD should ideally be administered during stable D 8.88 (1.26)
disease
Live attenuated vaccines should be avoided whenever possible in IV D 9.25 (1.13)
immunosuppressed patients with AIIRD
Vaccination in patients with AIIRD can be administered during the use of DMARDs II B 9.13 (1.02)
and TNF blocking agents, but should ideally be administered before starting B cell-
depleting biological therapy
Influenza vaccination should be strongly considered for patients with AIIRD III Ib Ib BC 9.00 (1.10)
23-valent polysaccharide pneumococcal vaccination should be strongly considered III Ib Ib BC 8.19 (1.38)
for patients with AIIRD
Patients with AIIRD should receive tetanus toxoid vaccination in accordance with II II BD 9.19 (1.11)
recommendations for the general population. In case of major and/or contaminated
wounds in patients who received rituximab within the last 24 weeks, passive
immunisation with tetanus immunoglobulin should be administered
Herpes zoster vaccination may be considered in patients with AIIRD III IV CD 8.00 (1.59)
HPV vaccination should be considered in selected patients with AIIRD III CD 8.44 (1.41)
In hyposplenic/asplenic patients with AIIRD, influenza, pneumococcal, Haemophilus IV D 9.50 (0.82)
influenzae b and meningococcal C vaccinations are recommended
Hepatitis A and/or B vaccination is only recommended in patients with AIIRD at risk II* III* D 9.13 (0.89)
Patients with AIIRD who plan to travel are recommended to receive their D 9.25 (1.24)
vaccinations according to general rules, except for live attenuated vaccines which
should be avoided whenever possible in immunosuppressed patients with AIIRD
BCG vaccination is not recommended in patients with AIIRD III D 9.38 (1.09)
*For hepatitis B only
AIIRD, autoimmune inflammatory disease; BCG, Bacillus Calmette-Gurin; DMARD, disease-modifying antirheumatic drug; HPV, human papillomavirus; TNF, tumour necrosis factor;
VAS, visual analogue scale; VP, vaccine-preventable.

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Recommendation

although no studies have been performed on efcacy and safety


Box 2 Vaccinations to be checked during the initial of swine u vaccination in patients with AIIRD. Because some
investigation (by history taking) of the swine u vaccines contain the adjuvant MF-59, an oil-in-
water emulsion that potentiates the humoral response, it is reas-
Haemophilus influenzae b suring that a large meta-analysis showed no difference in the
Hepatitis A occurrence of adverse events that were of autoimmune origin
Hepatitis B between persons vaccinated with inuenza vaccine with and
Human papillomavirus without MF-59.79
Influenza
Neisseria meningitides (6) 23-valent polysaccharide pneumococcal vaccination (23-PPV)
Rubella (for women of childbearing age) should be strongly considered for patients with AIIRD (grade of
Streptococcus pneumoniae evidence IbIII; strength of recommendation BC; Delphi vote 8.19)
Tetanus toxoid As stated above, patients with AIIRD are at increased risk of
dying from pulmonary infections compared with the general
population,2 4 5 72 with pneumococci being considered as one
vaccines might also be considered, but there are no studies to of the main causative pathogens. Pneumococcal vaccination
support this strategy. induces an adequate to slightly reduced humoral response in
patients with RA, SLE, psoriatic arthritis, ankylosing spon-
(4) Vaccination in patients with AIIRD can be administered during dylitis and SSc, even when treated with immunosuppres-
the use of disease-modifying antirheumatic drugs and tumour necrosis sive drugs.36 4245 47 5154 62 71 80 MTX, with or without TNF
factor blocking agents but should ideally be administered before blocking agents45 69 and, in particular, rituximab71 reduces the
starting B cell depleting biological therapy (grade of evidence IIa; humoral response following pneumococcal vaccination. It is
strength of recommendation B; Delphi vote 9.13) unknown if and when revaccination should take place and if
The efcacy of vaccination during the use of disease-modi- the new conjugated pneumococcal vaccines, whether or not in
fying antirheumatic drugs (DMARDs), glucocorticoids and/ combination with 23-PPV (so-called prime-and-boost strategy),
or tumour necrosis factor (TNF) blocking agents has been induce more and/or more durable immunity to pneumococci in
studied in patients with rheumatoid arthritis (RA), systemic patients with AIIRD. Pneumococcal vaccination seems safe in
lupus erythematosus (SLE), ANCA-associated vasculitis (AAV) patients with AIIRD, but again the available studies were not
and systemic sclerosis (SSc). Inuenza, pneumococcal, hepati- adequately powered for analysing safety.
tis B, tetanus toxoid and Haemophilus inuenzae b vaccination
were addressed. Most controlled studies showed responses (7) Patients with AIIRD should receive tetanus toxoid vaccination
in patients with AIIRD following vaccination comparable to in accordance to recommendations for the general population. In
those in healthy controls,24 25 3062 while some showed slightly case of major and/or contaminated wounds in patients who received
reduced efcacy.38 43 45 47 49 61 6367 Of note, azathioprine ham- rituximab within the last 24 weeks, passive immunisation with tetanus
pered the response following inuenza vaccination in patients immunoglobulins should be administered (grade of evidence II;
with SLE but the majority of patients still develop protective strength of recommendation BD; Delphi vote 9.19)
levels of antibodies.63 68 The combination of TNF blocking In patients with RA and SLE, efcacy for tetanus toxoid vac-
agents and MTX reduced the response to pneumococcal vac- cination has been demonstrated to be comparable with healthy
cination in patients with RA.45 67 69 Finally, humoral responses controls.30 46 58 59 This also holds true for patients with RA on
following inuenza vaccination 13 months after treatment immunosuppressive drugs, including those who have been
with rituximab41 70 78 as well as humoral responses following treated with rituximab 24 weeks earlier.71 However, since no
pneumococcal vaccination 28 weeks after treatment with ritux- data are available regarding the efcacy of tetanus toxoid vaccine
imab71 are severely hampered. Tetanus toxoid vaccination led to within 24 weeks after treatment with rituximab,71 we recom-
adequate immune responses 24 weeks after rituximab adminis- mend that patients with AIIRD who are treated with rituximab
tration.71 Vaccines should ideally be administered before B cell- less than 24 weeks earlier be passively immunised with tetanus
depleting biological therapy is started or, when patients are on immunoglobulins in case of a serious risk of contracting tetanus
such a treatment already, at least 6 months after the start but 4 (ie, in case of major and/or contaminated wounds).
weeks before the next course.
(8) Herpes zoster vaccination may be considered in patients with
(5) Inactivated influenza vaccination should be strongly considered AIIRD (grade of evidence IIIIV; strength of recommendation CD;
for patients with AIIRD (grade of evidence IbIII; strength of Delphi vote 8.00)
recommendation BC; Delphi vote 9.00) Compared with the general population, patients with RA, SLE,
Although the exact incidence of inuenza is unknown in AAV and polymyositis/dermatomyositis (PM/DM) have an
patients with AIIRD, their risk of dying from pulmonary infec- increased risk of developing herpes zoster.8199 RA is in itself
tions is increased.4 5 72 Inuenza vaccination has been shown to a risk factor, and the risk of developing herpes zoster is further
reduce admissions for and mortality from inuenza/pneumonia increased in patients with AIIRD treated with corticosteroids,
in elderly people with rheumatological diseases or vasculitis73 74 TNF blocking agents and non-biological DMARDs, particularly
and is efcacious in patients with RA, SLE, AAV and SSc, even cyclophosphamide, azathioprine and leunomide8285 90 91 98
when treated with DMARDs, iniximab, etanercept or adali- but not MTX.100 One study found an increased risk of herpes
mumab,2426 3041 4750 63 67 68 7577 but with rituximab as an zoster in patients with SLE when treated with rituximab.101
exception.41 70 78 Adverse events of inuenza vaccination in Lupus disease activity is not a risk factor for herpes zoster.88
patients with AIIRD seem comparable to those in healthy con- Herpes zoster vaccine has been shown to reduce herpes zoster
trols, although there are no studies that are sufciently powered and post-herpetic neuralgia in patients over 60 years,102 but no
with regard to safety. This recommendation regards seasonal studies have been performed in patients with AIIRD. Because
inuenza vaccination as well as pandemic swine u vaccination, of the high burden of herpes zoster in patients with AIIRD,

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Recommendation

herpes zoster vaccination may be considered in these patients, contracting these infections is increased (travel to or residence
but only when less severely immunosuppressed. The ACIP in endemic countries for hepatitis A and/or B); increased risk
suggested criteria for immunosuppressed patients who can of exposure or proven exposure to hepatitis A and/or B (eg,
receive herpes zoster vaccine; however, it must be emphasised because of medical profession, infected family member or
that these recommendations are not validated but are based on contacts), only when protective antibodies against hepatitis A
expert opinion and require further investigation.29 It seems pru- and/or B are absent.
dent to administer herpes zoster vaccine only to patients with
AIIRD who are seropositive for varicella zoster antibodies in (12) Patients with AIIRD who plan to travel are recommended to
order to prevent primary varicella infection with the vaccine receive their vaccinations according to general rules, except for live
strain. attenuated vaccines which should be avoided whenever possible in
immunosuppressed patients with AIIRD (no grade of evidence;
(9) Human papillomavirus vaccination should be considered in strength of recommendation D; Delphi vote 9.25)
selected patients with AIIRD (grade of evidence III; strength of It is unknown whether patients with AIIRD have an increased
recommendation CD; Delphi vote 8.44) risk of contracting travel-related vaccine-preventable infections
It has been shown that human papillomavirus (HPV) infection (VPI). In patients with RA and SLE, the risk of tuberculosis (TB)
occurs more often in patients with SLE, also with the high-risk is increased (also see recommendation 13).115129 However, the
(oncogenic) subtypes of the virus.103105 A lower percentage of majority of these TB cases represent reactivations from earlier
these infections (31.8%) is spontaneously cleared by patients contracted latent TB infection and Bacillus Calmette-Gurin
with SLE,106 leading to an increased risk of developing cervical (BCG) vaccination has not been clearly shown to prevent TB in
cancer. The risk factors for contracting HPV infection are the adults. Inuenza is endemic in subtropical and tropical climates
same in patients with SLE as in the general population.103 105 The during the entire year and is the most frequent VPI among trav-
efcacy of HPV vaccination has not been investigated in patients ellers to subtropical and tropical countries.130 131 The incidence
with AIIRD. HPV vaccination is recommended for young women of inuenza in patients with AIIRD is not known. Also the inci-
in many countries and should be considered for women with dence of cholera, diphtheria, hepatitis A, meningococcal infec-
SLE until the age of 25 years. The quadrivalent (q) HPV vaccine tion, poliomyelitis, rabies, tetanus, tick-borne encephalitis,
has been associated with venous thromboembolic events (VTE). typhoid fever and yellow fever is unknown. Studies addressing
However, of the 31 cases (0.2/100.000 doses of qHPV vaccine) the efcacy of inuenza vaccination (in patients with RA, SLE,
with objectied VTE, 90% had a known risk factor for VTE SSc and AAV)2426 3041 4750 63 67 68 7577 and tetanus toxoid vacci-
(antiphospholipid syndrome in two cases).107 nation (in patients with RA and SLE)30 46 58 59 generally showed
responses comparable to those in healthy controls. To protect
(10) In hyposplenic/asplenic patients with AIIRD influenza, patients with AIIRD from contracting travel-related VPI, they
pneumococcal, Haemophilus influenzae b and meningococcal C should receive the vaccinations that are recommended to the
vaccinations are recommended (grade of evidence IV; strength of general population. Exceptions are vaccinations with BCG
recommendation D; Delphi vote 9.50) vaccine, oral poliomyelitis vaccine, oral typhoid fever vaccine
Hyposplenic/asplenic patients are at risk of contracting a so- and yellow fever vaccine which contain live attenuated micro-
called overwhelming post-splenectomy infection (OPSI). OPSI organisms and therefore might lead to life-threatening infec-
is caused by encapsulated bacteria (eg, Streptococcus pneumoniae, tion in immunosuppressed patients with AIIRD.
H inuenzae b, Neisseria meningitidis) and the mortality of OPSI is
up to 70%.108112 OPSI can occur as a secondary infection after (13) BCG vaccination is not recommended in patients with AIIRD
infection with inuenza. No studies have addressed the efcacy (grade of evidence III; strength of recommendation CD;
of vaccination to prevent OPSI in patients who are hyposplenic/ Delphi vote 9.38)
asplenic, but the general consensus is to vaccinate these patients The incidence of TB is increased in patients with AIIRD, in par-
against inuenza, S pneumoniae, H inuenzae b and N meningitides ticular when treated with immunosuppressive drugs (DMARDs,
C.113 When hyposplenic/asplenic patients with AIIRD plan to corticosteroids),115119 121124 127129 especially TNF block-
travel to or live in areas where other meningococcal strains are ing agents.116119 122 127129 The large majority of these cases of
endemic (A, Y, W135), vaccination for these meningococcal sub- active TB are reactivations of earlier contracted latent TB infec-
types is also indicated.114 Prophylactic or on-demand antibiotics tions which cannot be prevented by vaccination. Moreover,
and preventive measures for malaria and babesiosis are beyond BCG vaccination has not been clearly demonstrated to be efca-
the scope of these recommendations. cious in preventing TB in adults. Finally, BCG vaccine contains
attenuated mycobacteria and vaccination with BCG vaccine
(11) Hepatitis A and/or B vaccination is only recommended in has been shown to induce BCG-itis in immunosuppressed
patients with AIIRD at risk (grade of evidence IIIII; strength of patients.132134
recommendation BD; Delphi vote 9.13)
Data on the incidence of hepatitis A and B infection in patients
with AIIRD are lacking. Reactivation of hepatitis B infection Research agenda
in patients with AIIRD has been described following treat- The EULAR Task Force for vaccination in patients with AIIRD
ment with immunosuppressive medication or immediately agreed on the research agenda as shown in table 2 in the online
after discontinuing immunosuppressive medication (includ- supplement.
ing TNF blocking agents). However, no comparative studies
have been published so it is impossible to distinguish whether DISCUSSION
the immunosuppressive treatment, the disease activity of the The recommendations for vaccination in patients with
AIIRD or the natural course of chronic hepatitis B infection AIIRD, as presented above, are based on the current evi-
was the cause of the hepatitis are. Hepatitis B vaccination is dence resulting from the systematic literature review and
efcacious in most patients with AIIRD.5557 Vaccination for the opinion of selected experts in the elds of rheumatology,
hepatitis A and/or B is only recommended when the risk of clinical immunology, nephrology, paediatric rheumatology/

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Recommendation

immunology and infectious diseases from 11 European coun- Author affiliations 1Department of Internal Medicine, Division of Infectious
tries. Unfortunately, no randomised controlled studies were Diseases, University Medical Centre Groningen, Groningen, The Netherlands
2The Zabludowicz Centre for Auto-immune Diseases, Sheba Medical Center,
available that addressed the efcacy of vaccination in patients Tel Hashomer, Israel
with AIIRD on clinical end points. The highest strength of 3Department of Internal Medicine F, Department of Rheumatology, Tel Aviv Medical

these recommendations is therefore B (see table 1 in online Center, Tel Aviv, Israel
4The Sackler Faculty of Medicine, Tel Aviv University, Israel
supplement). We did not systematically review the litera-
5Department of Auto-immune Diseases, Hospital Clnic, Barcelona, Spain
ture on vaccines in the general population without AIIRD, 6Department of Rheumatology, St. Jamess Hospital, Dublin, Ireland
but the experts did take into account their knowledge of this 7Department of Rheumatology, Hospital Cochin, Paris, France
wider literature in formulating the recommendations. In gen- 8Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine,

eral, it should be noted that, even for the general population, University of Leeds, Leeds, UK
9Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust,
conceptions about the efciency and efcacy of vaccination
Leeds, UK
have varied over time. There is strong evidence that adequate 10Department of Rheumatology, Lund University Hospital, Lund, Sweden
immune responses are achieved with vaccines, especially 11Stanford Prevention Research Center, Stanford University School of Medicine,

for inuenza and pneumococcal vaccines, but this may not Stanford, USA
12Department of Hygiene and Epidemiology, School of Medicine, University of
always translate into equally high efciency at the clinical
protection level.135137 Ioannina, Ioannina, Greece
13Department of Medicine, Tufts University School of Medicine, Boston, USA
Other infection-preventive measures than vaccination are not 14Harvard School of Public Health, Boston, USA
addressed in these recommendations, and we suggest a new 15Renal Unit, Addenbrookes Hospital, Cambridge, UK
16Department of Rheumatology and Clinical Immunology, University Medical Center
EULAR task force should be set up to recommend on important
issues such as general hygienic measures and antibiotic prophy- Groningen, Groningen, The Netherlands
17Department of Rheumatology and Clinical Immunology, Justus-Liebig Universitt
laxis for patients with AIIRD to further reduce infection-related Giessen, Bad Nauheim, Germany
morbidity and mortality in patients with AIIRD. 18Department for Scientific Research, Bezhanijska Kosa University Medical Center,

Our literature search focused essentially on three important Belgrade, Serbia


19Department of Medicine, Sapienza Universit di Roma, Rome, Italy
aspects of vaccination in patients with AIIRD: the incidence
20Department of Pediatric Immunology, University Medical Center Utrecht, Utrecht,
of infectious diseases for which vaccines are available; the
The Netherlands
efcacy of vaccinations that are indicated; and the harms of
vaccination. We should acknowledge that the grading of the Funding EULAR.
available evidence can differ between the three aforemen- Competing interests None.
tioned aspects: often little evidence is available for the inci- Provenance and peer review Not commissioned; externally peer reviewed.
dence of VPI and most studies are underpowered with regard
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EULAR recommendations for vaccination in


adult patients with autoimmune inflammatory
rheumatic diseases
S van Assen, N Agmon-Levin, O Elkayam, R Cervera, M F Doran, M
Dougados, P Emery, P Geborek, J P A Ioannidis, D R W Jayne, C G M
Kallenberg, U Mller-Ladner, Y Shoenfeld, L Stojanovich, G Valesini, N M
Wulffraat and M Bijl

Ann Rheum Dis 2011 70: 414-422 originally published online December
3, 2010
doi: 10.1136/ard.2010.137216

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Material http://ard.bmj.com/content/suppl/2010/10/06/ard.2010.137216.DC1
http://ard.bmj.com/content/suppl/2017/03/20/ard.2010.137216.DC2
http://ard.bmj.com/content/suppl/2017/03/20/ard.2010.137216.DC3
References This article cites 129 articles, 38 of which you can access for free at:
http://ard.bmj.com/content/70/3/414#BIBL

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Topic Articles on similar topics can be found in the following collections


Collections Immunology (including allergy) (5144)
Connective tissue disease (4253)
Musculoskeletal syndromes (4951)

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